DESCRIPTION (Adapted from the applicant's abstract and specific aims): Tumor necrosis factor alpha (TNFa) has been implicated in many human disease processes especially those involving the lung as macrophages appear to be important target cells. TNFa is recognized by the cell surface receptors CD120a, (p55) and CD120b (p75). Ligation and aggregation of CD120a (p55) are necessary for the induction of the majority of cellular responses to TNFa including the induction of nitric oxide and insulin-like growth factor-1 expression by macrophages. Several signal transduction mechanisms have been reported to be activated in response to activated TNFa including a kinase cascade that mediates the activation of p42mapk/erk2. It is not known how this kinase cascade is coupled to CD120a (p55). It is hypothesized that signalling through CD120a (p55) is initiated by the phosphoproteins pp95 and/or pp120 which, through their intrinsic association with the intracellular domain of CD120a (p55), enable communication between the receptor and the distal kinase signaling cascade via RAS. The specific aims are: 1) to purify and clone the phosphoproteins, pp95 and pp120, that are constitutively associated with the intracellular domain (ICD) of CD120a (p55); 2) to investigate the functions of pp95 and pp120 and to define the region(s) within the ICD of CD120a (p55) that interact with pp95 and pp120; and 3) to determine the upstream kinase(s) and signalling components responsible for activating p42mapk/erk2.